Injectable pharmaceutical composition

ABSTRACT

Formulations of programmed-release medicinal products intended for parenteral administration by injection, comprising calibrated solid microspheres (1 to 300 microns) of active substances. Provided in this form, steroids (for example progesterone and 17-β-estradiol) may constitute injectable contraceptives, and the action of drugs having an approximatively 24 hours lasting effect may be regulated and extended.

This is a continuation of U.S. patent application No. 08/243,823, filedMay 17, 1994, now U.S. Pat. No. 512,303 which is a divisional of U.S.patent application No. 07/714,583, filed Jun. 13, 1991, now U.S. Pat.No. 5,360,616.

FIELD OF THE INVENTION

The present invention relates to a process for improving the control ofthe pharmacokinetic and pharmacological properties of pharmaceuticallyactive substances. It relates also to particles of active substances,and their use in delayed-release injectable formulations.

PRIOR ART

Biologically active substances, weakly soluble in a physiologicalmedium, have already been used in the form of a suspension of particlesand administered by intramuscular injection in order to obtain a slowdissolution and therefore a prolonged effect in the human or animalorganism. For example, mixtures of norethisterone and mestranol, in theform of crystalline powder in aqueous suspension, have been tested forthe manufacture of an intramuscular injectable contraceptive (J. GarzaFlores et al., Contraception, May 1988, Vol. 35, No. 5, 471-481).

Probably because of particle size variations and particle shapeirregularities, these prior art compositions generally exhibit severaldefects:

Curve for the release of active substances exhibiting a sharp peak Justafter the injection and then a descending slope, which increases thetotal dose necessary to obtain an adequate, lasting effect.

Occasional formation of lumps or crusts in the suspension.

Necessity to use large diameter hypodermic needles in order to avoid therisk of a blockage in the syringe outlet.

The patent FR 2 070 153 (DUPONT DE NEMOURS) describes suspensions ofparticles of active ingredients coated with polylactide polymermatrices. This technique decreases the initial medicament shock effectand slows the release of the active substance. However, the shapeirregularities create, in this case as well, a risk of operativeincident at the time of injection, and the variations in shape, size andinternal composition of these particles cause an undesirable variabilityin the rates of dissolution in the receiving organism, that is to say adispersion of results which does not permit a precise pharmacokineticprediction.

The patent EP No. 257 368 (AMERICAN CYANAMID CO) describes a compositionfor parenteral use consisting of microspheres of fats and/or waxes, ofnatural or synthetic origin, of low melting point (40°-60° C.), loadedwith particles of a polypeptide, for example a growth hormone. Whenthese compositions are injected into cattle, the dissolution of thegrowth hormone is delayed by the wax or fat coating, which prolongs itspresence in the animal organism, causing an increase in growth or inlactation. These microspheres have a tendency to deform, to agglutinateor to coalesce when the ambient temperature is high, particularly intropical countries (40°-60° C.), which may cause handling or storageproblems. As the proportion of active polypeptide in the particle islimited in practice to 30-40%, the injection of these particles also hasthe disadvantage of introducing into the organism a quantity of carriersubstance which is foreign and useless to this organism, and which is atleast of the order of 1.5-3 times that of the active substance.

Several coating or microencapsulation techniques have been used in theprior art, part of which is described for example in "Encyclopedia ofChemical Technology, 3rd edition, volume 15, pages 470 to 493 (1981),JOHN WILEY AND SONS. The microcapsules thus formed often contain"central" particles of very different size, or no central particle atall. The prior art microspheres or microcapsules permit a slowdissolution and therefore an overall delayed release of the activeingredients. However, given the shape and mass heterogeneities of thecentral particles or of dispersed ultra-fine particles which may becoated in capsules of similar external dimension, the rate of release ofthe active Ingredient is not homogeneous and a fine control of therelease, or a finely programmed release as a function of time is notpossible.

Furthermore, from a pharmacological point of view, the reproducibilityand the reliability of the results obtained with these prior artpreparations are not adequate for certain applications, for examplecontraception, which constitutes an obstacle to their practical use on alarge scale.

Such a programmed release is desirable nevertheless, in particular whenthe action of the biologically active substance has to coincide with anatural biological cycle of the human or animal organism (for examplemenstrual) or when it is important (for example in the case of ananalgesic, an alkaloid, a cardiotonic and the like) that the rates ofrelease are well controlled in order to avoid any period of overdose oron the contrary of underdosage at the time of an injection subsequent toan earlier injection.

SUMMARY OF THE INVENTION

The aim of the present invention is to provide delayed-releaseformulations for administration by parenteral injection, intended forexample for the applications mentioned in the preceding paragraph, whichallow a fine control of this release without exhibiting thedisadvantages of particle suspensions or of microcapsules of the priorart.

This aim is achieved by virtue of the use of solid, non-porous andcalibrated microspheres consisting substantially of pharmaceuticallyactive substances.

The rate of dissolution of a microsphere in a given solvent medium(preferred target medium: the internal physiological medium) isessentially a function of the radius of the sphere, taking intoconsideration the relationships between volume, area and radius of asphere.

According to one aspect of the present invention, the use of solid,non-porous spheres makes it possible to have a precise knowledge of themass-surface relationship of particles and therefore, by virtue of aselection of the size of the spheres, that is to say of the radius or ofa distribution of radii, to have a precise control of the rate ofrelease of the active ingredient or active ingredients administered.This control precision, by avoiding overdosages or the need tocompensate for underdosages, makes it possible to reduce the totaladministration of the biologically active substance or active substancesto the minimum quantity required in order to obtain the desiredtherapeutic effect and thereby decrease the risk of producingundesirable secondary effects in the patient.

Used in the form of pure active ingredients, the microspheres accordingto the present invention have the advantage, compared to the coated ormicroencapsulated particles of the prior art, of decreasing the volumeof solid material which has to be injected into a living organism. Theyfurther have the advantage of not using a low-melting excipient (m.p.<60° C.), those particles could agglutinate and cause handling problemsupon injection.

They also have the advantage of not introducing unnecessary solidexcipient, more or less degradable, into the organism.

Some substances may be combined with adjuvants not directly active onthe receiving organism: the combination may comprise variouspharmaceutically acceptable additive means for increasing the stabilityor chemical integrity of the biologically active substances, it beingunderstood that they are not vector type excipients. In particular, itmay become useful to decrease the melting point or to inhibit adecomposition reaction during the microsphere manufacturing process (forexample by melting-freezing).

Relative to suspensions of pure active ingredients in the form ofparticles of irregular shapes known in the prior art, the microspheresaccording to the present invention have the advantage of a lessertendency to agglutinate and of passing in a more fluid manner through ahypodermic needle. Moreover, microspheres may be classified andseparated more finely and more reliably as a function of their size thanirregularly shaped particles.

The formulation according to the present invention may be provided inthe form of microsphere powder in vials-ampoules ready for making into asuspension, or in the form of a suspension ready prepared in injectableampoules ready for administering in human or veterinary medicine. Thesuspension medium may be water, a saline solution, an oil containing thebuffers, surfactants or preservatives conventionally employed ininjectable suspensions by pharmaco-technicians, or any other substanceor combination which does not threaten the physical and chemicalintegrity of the substances in suspension and which is suitable for theorganism which will receive it. If it is desired to avoid a suddeninitial elevation of the level of active ingredient in the internalmedium of the receiving organism, the use will be preferred, in the caseof ready-for-use suspensions, of liquid vectors in which the said activeingredients are practically insoluble. In the case of active substancespartially soluble in the lukewarm liquid vector but insoluble at coldtemperature, it is preferable, from the pharmacological point of view,to avoid the formation of precipitates (called "caking" effect) bypreparing formulations in the form of separate microsphere powder andliquid vector which will be mixed only at the time of injection.

In veterinary applications where the duration of desired effect may bevery long (for example lactation period of the adult female), diametersof some hundreds of microns may be used. If it is desired to limit thediameter of needles for injection syringes for the comfort of thepatient, it is good to limit the diameter of the microspheres to 300microns and more preferably to 100 microns. In contrast, for very shortdurations of desired effect (for example circadian), the diameter of themicrosphere may be reduced to 1 micron.

For most applications in human medicine (duration of action of theactive ingredient between a circadian cycle and a menstrual cycle), itis preferable to use microspheres whose diameter is between 5 and 100microns depending on the active substances.

An essential condition for achieving the dosage form according to thepresent invention is to have batches of calibrated microspheres, that isto say homogeneous in diameter. If necessary, a separation of themicrospheres according to their diameter may be carried out during themanufacture using known processes: for example by cyclonic separators,by sieving using air suction or by sieving in a liquid medium. Inpractice, it is sufficient if more than 70% of the microspheres havediameters of between 70% and 130% of a specified diameter. If necessary,the ideal dissolution curve, determined by the proposed application, maybe approached by mixing batches with different suitable diameters.

Processes for preparing a solid product in the form of microspheres bymechanical abrasion are known in the state of the art. Other processesuse for example the suspension of the product in the melted state in theform of microdrops, with stirring, in a liquid vector with which thesaid product is non-miscible, followed by solidification of the saidproduct. The patent WO 90/13285 describes a process for the manufactureof porous microspheres obtained by spraying, freezing and freeze-dryingin a cold gas substances dissolved in a suitable solvent. In order toobtain solid and non-porous microspheres according to the presentinvention, it has been preferred to develop, for substances which may bemaintained in a chemically stable state above the melting point, aprocess which consists in spraying under pressure and/or by means of hotgas the substance (optionally with additives) in the melted state andrapidly freezing the cloud thus formed in a cold gas.

Furthermore, the particles which are not in compliance with thespecifications may be recycled.

Taking into consideration the conditions of use, from a pharmacologicalpoint of view, the formulations according to the present invention areparticularly suited to substances whose melting temperature is greaterthan 60° C. and which are thermostable above their melting point (orwhich may be made thermostable by means of additives) in order to beable to undergo the manufacturing process. An additive may also be usedin order to eliminate a phase transition, from a solid phase to anothersolid phase, which is likely to weaken the structure of the sphere. Theprocess is also suited to mixtures of active substances in solidsolution one inside the other.

The present invention will be better understood by means of the figuresand examples below. However it is not limited to these embodiments, butonly by the content of the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the schematic of the manufacture of microspheres accordingto the present invention.

FIG. 2 shows progesterone microspheres (mean diameter=50 μm-100 μm).

FIG. 3 shows 17-β-estradiol microspheres (mean diameter=100 μm).

FIG. 4 shows the particle size distribution of a fraction (meandiameter=25 μm) of cholesterol spheres.

FIG. 5 represents an experimental setup for determining the rate ofdissolution of microspheres.

FIG. 6 shows the comparative dissolution profiles of microspheres andprogesterone crystals (50-125 pm).

FIG. 7 shows the comparative dissolution rates of progesteronemicrospheres and crystals (derivatives of optical absorbance versustime).

FIGS. 8 and 9 shows the comparative dissolution profiles of17-β-estradiol microspheres and crystals (50 to 100 μm).

FIGS. 10 and 11 show the comparative dissolution profiles ofprogesterone microspheres and crystals (50 to 100 μm).

FIGS. 12 and 13 show the comparative dissolution profiles of naproxenmicrospheres and crystals (50-100 μm).

FIGS. 14, 15 and 16 show the plasma levels (rabbits) obtained withprogesterone by injection of an oil solution of crystals of mean size 44μm and of microspheres of mean size 44 μm respectively.

FIGS. 17, 18 and 19 show the plasma levels (rabbits) obtained with17-β-estradiol by injection of an oil solution of crystals and ofmicrospheres respectively.

FIG. 20 shows the plasma levels (rabbits) obtained with naproxen byinjection of a solution (curve 0) of crystals (curve 1) and ofmicrospheres (curve 2) respectively.

FIGS. 21 and 22 show the comparative dissolution profiles ofindomethacin microspheres and crystals (50-100 μm).

In the FIGS. 6-13, and 20-22, the time scales are given in hours; in theFIGS. 14-19, the time scales are given in days, after injection.

Example 1: manufacture of progesterone microspheres.

We refer to FIG. 1. Preheated nitrogen under pressure is fed by theinlet tube A 1 into the spray device and crosses a thermoregulatedheating zone B where it is brought to a temperature of between 125° and130° C. before being admitted into the sprayer D. The sprayer D isconnected by a pipe to a heated chamber C in which the progesterone ismaintained in the melted state (T=130° C.) and under nitrogen pressure(inlet A₂). It is carried by the nitrogen current and mixed with thelatter in order to be sprayed into a cloud by the outlet nozzle of thesprayer D and penetrates into the spraying-freezing chamber F. Areservoir E contains liquid nitrogen which evaporates and penetrates byseveral tubings in the form of ultra-cold gas, at high speed, into thespraying-freezing chamber F where it meets the progesterone cloud.Immediately after their formation by the sprayer, the droplets aresurrounded by a current of ice-cold gas which crystallises them intomicrospheres and prevents them from touching the side walls before theircomplete solidification. The temperature at the outlet of thespraying-freezing chamber is between -15° C. and -50° C. All themicrospheres produced by means of this chamber F have a perfectspherical shape. At the outlet of the chamber F are two cyclonicseparators G₁ and G₂ (of known construction moreover) mounted in series.0. The microspheres are recovered in collecting vessels H₁ and J₂ ; atthe outlet of the cyclones, the gases pass through a decontaminatingfilter I in which a slight vacuum relative to the existing pressureprevailing in the first cyclone is maintained by means of a pump. FIG. 2shows a microphotograph of a fraction (diameter=50 μm to 100 μm) ofrecovered progesterone microspheres (in an electron microscope).

The IR spectra of the raw material (crystals) and of the microspheresobtained have the same peaks, the UV spectra are similar and thethermograms are practically identical (mp of crystals=130° C., mp ofmicrospheres=129°); no structural degradation of the progesteronetherefore occurred during the process.

Example 2:

The same operating conditions (except that mp=185° C.) are applied tothe manufacture of 17-β-estradiol microspheres with the same results.

FIG. 3 shows a microphotograph of a fraction of these microspheres, ofmean diameter 100 μm.

Example 3: Particle size distribution.

Cholesterol microspheres are manufactured by the same operating processas in Example 1. After separation, the fraction of mean diameter 25 μmexhibits the particle size distribution shown in FIG. 4.

Example 4: Manufacture of naproxen microspheres.

The process in Example 1 is used. Operating conditions:

Melting: 160° C. in nitrogen atmosphere.

Sprinkling: by valve with air pressure of 2.0 psi (140 g/cm²)

Freezing: by air at -20° C., under pressure of 4 kg/cm².

Recovery: by cyclones

Selection: in aqueous medium and by screening according to particlesize.

Example 5: Progesterone microspheres

The process in Example 1 is used. Operating conditions:

Melting: 130° C. in nitrogen atmosphere.

Sprinkling: by valve, with air pressure of 0.5 psi (70 g/m²)

Freezing by air at -20° C., under pressure of 4 kg/cm²

Recovery: by cyclones

Selection: in aqueous medium and by screening according to particlesize.

Example 6: 17-β-estradiol

The procedure in Example 1 is used. Operating conditions:

Melting: 180° C. in nitrogen atmosphere.

Sprinkling: by valve, with air pressure of 2.0 psi (140 g/cm²)

Freezing: by air at -10° C., under pressure of 3 kg/cm²

Recovery: by cyclones

Selection: in aqueous medium and by screening according to particlesize.

Example 7: indomethazin microspheres

The procedure in Example 1 is used. Operating conditions:

Melting: 165° C. in nitrogen atmosphere.

Sprinkling: by valve, with air pressure of 1.5 psi (110 g/cm²)

Freezing: by air at -20° C., under pressure of 4 kg/cm²

Recovery: by cyclones

Selection: in aqueous medium and by screening according to particlesize.

Comparative UV and IR spectrophotometric analysis before and afterformation of microspheres.

It is necessary to check that no chemical damage of the substancesoccurs during the spray-freezing process, which could modify theirtherapeutic properties. The starting materials (crystals) and themicrospheres obtained by spray-freezing are compared by UV and IRspectophotometry. UV spectras shall always be superimposable and IRspectras shall correspond. If differences in infrared spectras appear,it shall be checked if they are due to a polymorphism phenomenon, bymeans of an HPLC setup with diode-array detection. Differential thermalanalysis is also used, not only to check the melting points, but also todetermine if endothermic or exothermic transitions occur, due either tostructure modifications or to a polymorphism, which may influence themicrosphere information process, or due to heat-induced chemicalreactions.

Equipment used in ultraviolet spectography: Hewlett Packard model 8452Awith photodiode arrangement and quartz cell with a beam of 0.1 cm.

Solvents: ethanol for 17-beta-estradiol, progesterone and cholesterol;0.1 N HCl for naproxen, 0.1 N sodium hydroxide for indometacin.

The results show no trace of modification.

Equipment used in infrared spectrophotometry: Beckman Acculab 10.Dispersion medium: potassium bromide.

Chromatography: HPLC device with photo diode-array detector, modelWaters 990 and Nec powermate 2 workstation.

The results show no modification after the formation of microspheres forindometacin, progesterone, 17-beta-estradiol and naproxen.

Thermal analysis: Shimadzu DSC 50 calorimeter and CR4A workstation.

On the differencial thermograms, the measured melting points do not showany chemical degradation of the substances (for example MP crystals=130°C., MP microspheres=129° C. for progesterone). The thermograms ofprogesterone and 17-β-estradiol show only a morphological modificationof the solid crystalline faces.

Example 8:

Dissolution curves progesterone microspheres.

The tests may be carried out either in pure water or in a 1:1water-polypropylene glycol medium in order to accelerate thedissolution. The experimental setup is shown in FIG. 5. An infusion cell1, containing the sample, is fed by a reservoir (stirred) of dissolutionmedium 2; both are kept on a water bath 3. The optical density of themedium at 240 nm is recorded by a spectrophotometer 4 and the medium isreturned into the reservoir. A bubble trap 5 and a peristaltic pump 6complete the circuit.

FIG. 6 shows the dissolution profiles of crystals (curve 1) andmicrospheres (curve 2) of the same particle size (50-125 μm) measured bythe variation of optical absorbance-versus time. The test is carried outin a water/PPG 50:50 medium. It appears that the dissolution ofmicrospheres is slower than the dissolution of crystals. FIG. 7 showsthe rates of dissolution (derivatives of the variations of opticaldensity versus time) of crystals (1) and microspheres of the same meanparticle size (about 150 μm). The particle size distribution of thecrystals is more heterogeneous and their dissolution profile is moreirregular than that of the microspheres.

Example 9

The same test as in Example 8 is carried out with 17-β-extradiol. Theresults (not shown) are similar. The following examples show theComparative reproducibility of the initial parts of the dissolutioncurves of crystals and microspheres of comparable size, for the sameproduct. The equipment used is the one in FIG. 5. Several (3-6)measurement circuits (dissolution cells and tubings) containingidentical samples are processed in parallel by the same peristatic pumpand measured simultaneously.

Example 10:

Dissolution of progesterone crystals: (FIG. 11)/progesteronemicrospheres (FIG. 10)

Dissolution medium used: H₂ O HPLC quality with 0.01% of Tween 80

Sample: 50 mg

Particle size: 50 to 100 microns

Sampling intervals: 0,2,4,8,14,20 hours

Spectrophotometric wavelength: 240 nm

Example 11:

Dissolution of naproxen microspheres: (FIG. 12)/naproxen crystals (FIG.13)

The equipment used is that in FIG. 5.

Dissolution medium used: H₂ O HPLC quality with 0.01% of Tween 80

Sample: 50 mg

Particle size: 50 to 100 microns

Sampling intervals: 0,1,3,6,9,12,24 hours

Spectrophotometric wavelength: 232 nm

Example 12:

Dissolution of 17-beta-estradiol microspheres: (FIG.9)/17-beta-estradiol (FIG. 8).

The equipment used is that in FIG. 5

Dissolution medium used: H₂ O HPLC quality with 0.01% of Tween 80

Sample: 50 mg

Particle size: 50 to 100 microns

Sampling intervals: 0,2,4,18 hours

Spectrophotometric wavelength: 282 nm

All the curves show that the reproducibility of the results and theregularity of the dissolution profiles are better for the microspherebatches than for the crystal batches in the initial part of thedissolution process (which is the most critical moment).

Example 13: injectable formulations

    ______________________________________                                        Formula No. 1                                                                 Progesterone microspheres                                                                          75         mg                                            Polyethylene glycol 800                                                                            20         mg                                            Carboxymethylcellulose sodium                                                                      1.66       mg                                            Polysorbate 80       2.0        mg                                            Propylparaben        0.14       mg                                            NaCl                 1.2        mg                                            H.sub.2 O cbp        1          ml                                            Formula No. 2                                                                 17-beta-estradiol microspheres                                                                     2.5        mg                                            Polyethylene glycol 800                                                                            20         mg                                            Carboxymethylcellulose sodium                                                                      1.66       mg                                            Polysorbate 80       2.0        mg                                            Propylparaben        0.14       mg                                            NaCl                 1.2        mg                                            H.sub.2 O cbp        1          ml                                            Formula No. 3                                                                 Naproxen microspheres                                                                              100        mg                                            Carboxymethylcellulose sodium                                                                      5.0        mg                                            Polysorbate 80       4.0        mg                                            NaCl                 9.0        mg                                            Benzyl alcohol       9.0        mg                                            H.sub.2 O cbp        1          ml                                            ______________________________________                                    

Example 14: Study of the plasma levels of progesterone in rabbits (FIGS.14, 15, 16)

The study comprises the comparative evaluation of the effect on theplasma levels in rabbits produced by the parenteral administration ofprogesterone in the form of an oil solution (0), an aqueous suspensionof crystals (1) and an aqueous suspension of microspheres (2) (FormulaNo. 1, mean particle size: 44 μm).

A single intramuscular dose of progesterone is administered to 10 malerabbits of New Zealand breed of an average weight of 3.5 kg.

The sampling interval is 1,2,4 and 24 hours for 20 days and then everythree days up to 30 days.

The 2-ml samples, taken by venopuncture, are centrifuged and kept at-20° C. until their analysis by radioimmunoassay.

Example 15: Study of the plasma levels of estradiol in rabbits (FIGS.17, 18, 19)

The study comprises the comparative evaluation of the effect on theplasma levels in rabbits produced by the parenteral administration ofestradiol in the form of an oil solution (0), an aqueous suspension ofcrystals (1) and an aqueous suspension of estradiol microspheres (2)(particle size 50-100 μm, Formula no.2).

A single intramuscular dose of 5 mg of estradiol is administered to 8male rabbits of New Zealand breed of an average weight of 3.5 kg.

The sampling interval is 1,2,4 and 24 hours for 20 days and then everythree days up to 30 days.

The 2-ml samples, taken by venopuncture, are centrifuged and kept at-20° C. until their analysis by radioimmunoassay.

Example 16: Comparative evolution of plasma levels of naproxen inrabbits.

Experimental animals: rabbits of New Zealand breed aged about 5 monthsand weighing on average 3.7 kg.

The reference sample is 5 ml of blood taken by cardiac puncture,followed by the intramuscular administration of 2 ml of the test formula(No 3) into the lower right leg.

The analytical samples were taken at intervals of 30 min for 2 hours andat intervals of 60 min up to the end of 6 hours. In some cases,depending on the kinetic characteristics of the medicinal product,additional samples were taken.

2-ml analytical samples, also taken by cardiac puncture, were placed ina Vacutainer, heparin added, centrifuged at 3000 rpm for 10 min and theplasma separated and frozen in cryotubes at -20° C. until theiranalysis.

FIG. 20 shows that the variation of the plasmatic levels, obtained afterinjection of microspheres is much more regular than that obtained afterinjection of random shave particles (50-100 μm).

In summary, the above disclosed resuts show that in the initial part ofthe dissolution process, pharmaceutically active substances exhibit muchmore reproducible numeric values and much more smoother profiles, inform of batches of calibrated microspheres than in form of random shapedparticles. This allows to calculate more accurately a pharmaceuticallyefficient dose. Moreover, the disappearance of the initial dissolutionpeak (or at least its dramatic decrease, if compared with crystals orrandom particles) as well as the delayed and globally extendeddissolution process permits to calculate increased unit doses intendedto be administered at more spaced periods of time.

Furthermore the above disclosed results show that this type of structuremay be used as well for the manufacture of drugs those efficiency-periodis relatively short, that is several hours to a few days (for exampleanalgesics), as well as for substances those intended efficiency-periodlasts a few weeks. Among the latter, one may cite in particular the useof sexual hormones (as progesterone or 17-β-estradiol) for themanufacture of a contraceptive intended for monthly parenteral injectionor for the manufacture of a post-partum contraceptive, or for themanufacture of a medicinal product for parenteral injection intended forthe prevention of ostheoporosis in menopausal women.

The manufacturing process described above, the spherical structures andthe formulations obtained and their use by the parenteral route byinjection are naturally not limited to the substances given as examplesabove, but are applicable to all pharmaceutically active substances,chemically stable during the micronisation, on the condition that thepharmaceutical modifications which permit the microspheres (brief orlong duration depending on the diameter, regularisation of the plasmaprofiles) possess a therapeutic advantage or one of convenience and thatthe doses to be administered do not exceed a reasonable volume.Depending on the intended application, the method of adminstration maybe chosen from among hypodermic injection, subcutaneous injection,intramuscular injection, intra-articular injection, and intra-rachidianinjection.

We claim:
 1. Solid, non-porous microspheres for administration to areceiving organism said microspheres having a diameter in the range of1-300 μm, and consisting essentially of:an injectable analgesic thatundergoes a decomposition reaction below the melting temperature of saidanalgesic; and an adjuvant not active on the receiving organism butwhich, when mixed with the analgesic, decreases the melting point of theanalgesic below its decomposition temperature and wherein saidmicrospheres are obtained by spraying a mixture of said analgesic andadjuvant in the melted state to form droplets and rapidly freezing saiddroplets.